News Beyond Our Pages
Authors: Marc E. Rothenberg, Jean Bousquet
Journal: Journal of Allergy and Clinical Immunology (2018)

In the United States several minority populations have increased asthma prevalence and mortality and decreased bronchodilator drug response (BDR) to albuterol compared with white subjects. To elucidate the underlying molecular mechanisms, Mak et al (Am J Respir Crit Care Med 2018; https://doi.org/10.1164/rccm.201712-2529OC) performed a pharmacogenetics study of albuterol BDR in 1441 pediatric subjects of Puerto Rican, Mexican, and African American descent with asthma who had either high or low BDR to albuterol. Whole-genome sequencing analysis revealed both population-specific and shared genetic variants that were associated with higher BDR. These variants were present in loci near genes associated with lung capacity, immunity, and β-adrenergic signaling. Additionally, a BDR-associated variant, the NFKB1 gene, was found to have regulatory function in bronchial smooth muscle cells by using in vitro functional analysis. Although independent studies still need to be performed to replicate these rare variant associations, the authors have identified genetic variants in minority populations associated with differential responses to albuterol, which might lead to more targeted and improved treatment of pediatric asthma in racially and ethnically diverse populations in the future.Genetic variants in minority populations associated with differential responses to albuterol Genetic variants in minority populations associated with differential responses to albuterol The dose of inhaled glucocorticoids is often increased at the first sign of loss of asthma control to prevent progression to a full-blown exacerbation, although evidence behind this practice is limited. Two recent independent studies have been conducted to address this knowledge gap. Jackson et al (N Engl J Med 2018;378:891-901; https://doi.org/10.1056/NEJMoa1710988) performed a double-blind, placebo-controlled randomized trial involving 254 patients aged 5 to 11 years with mild-to-moderate persistent asthma and at least 1 exacerbation within the past year requiring treatment with systemic glucocorticoids. All subjects received daily low-dose inhaled glucocorticoids and were randomly assigned to continue the same dose (low-dose group) or use a quintupled dose (high-dose group) for 7 days at early signs of loss of asthma control. After 48 weeks, the authors did not observe a significant difference in the rate of severe asthma exacerbations between the 2 groups (0.37 exacerbations per year in the low-dose group and 0.48 exacerbations per year in the high-dose group, P = .30). The second study by McKeever et al (N Engl J Med 2018;378:902-10; https://doi.org/10.1056/NEJMoa1714257) was an unblinded real-life randomized trial with both adult and adolescent patients with asthma receiving inhaled glucocorticoids with a history of at least 1 exacerbation within the past year. One thousand eight hundred seventy-one patients were randomized to continue their usual management plan or quadruple the dose of inhaled glucocorticoids at the first sign of lack of asthma control. McKeever et al found that quadrupling the dose minimally decreased the number of patients with an asthma exacerbation in the following year (45% vs 52%, P = .002). However, adrenal suppression was similar to that of an oral course of prednisolone. These 2 studies demonstrate collectively that 4- or 5-fold increases in inhaled glucocorticoid doses do not robustly prevent asthma exacerbations and that further study into alternative strategies is necessary to prevent asthma exacerbations.Four- or 5-fold increases in inhaled glucocorticoid doses do not robustly prevent asthma exacerbations Four- or 5-fold increases in inhaled glucocorticoid doses do not robustly prevent asthma exacerbations Allergic diseases are associated with excessive immune responses to harmless environmental molecules, although the underlying mechanisms are still being dissected. Gour et al (Sci Immunol 2018;3; https://doi.org/10.1126/sciimmunol.aam9841) have identified a novel pathway that counterregulates these responses. Signaling through the epithelial surface receptor dectin-1 inhibited release of IL-33 in experimental murine models of aeroallergy and shrimp-induced anaphylaxis, leading to diminished recruitment of group 2 innate lymphoid cells and development of type 2 immune responses. These findings are generalizable to human subjects because this pathway exhibited decreased activity, with resultant increased IL-33 release, in primary respiratory epithelial cells derived from human patients with asthma or chronic rhinosinusitis compared with healthy control subjects. Additionally, a genetic association was identified between a genetic variant in the dectin-1 gene locus that decreases its expression and is associated with impaired pulmonary function in 2 independent cohorts of patients with asthma. Molecular analysis revealed that invertebrate tropomyosin, a molecule widely expressed in arthropods, including dust mites and shrimp, activated the dectin-1 receptor to prevent aberrant IL-33 release and type 2 immunity. In total, these results demonstrate that dectin-1 receptor activity is critical to restraining the development of aeroallergy and shrimp-induced anaphylaxis. Image used via Wikimedia Commons, created by user Rafael Ortega Díaz - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=1360107.Dectin-1 receptor activity is critical to restraining the development of aeroallergy Dectin-1 receptor activity is critical to restraining the development of aeroallergy We asked coauthors Marsha Wills-Karp, PhD, and Stephane Lajoie, PhD, of the Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, to comment on the study. He writes, “One of the major questions in allergy is why some subjects have inflammatory responses to generally innocuous environmental substances. This also means that the majority of subjects, who do not have asthma or other allergies, sense their environment differently than those with allergic diseases. We discovered a new pathway of protection mediated by dectin-1 to sense a common environmental protein to prevent aberrant inflammation at mucosal surfaces.” The anti-IgE antibody omalizumab has shown progress as an adjunctive therapy to oral immunotherapy to induce desensitization to individual food allergies, but it has not been studied in the context of multiple food allergies. Andorf et al (Lancet Gastroenterol Hepatol 2018;3:85-94; https://doi.org/10.1016/S2468-1253(17)30392-8) performed a double-blind, phase 2, placebo-controlled trial to test whether omalizumab decreases reactions in patients with multifood allergy aged 4 to 15 years. Forty-eight subjects were randomized to receive subcutaneous omalizumab (n = 36) or placebo (n = 12) for the first 16 weeks of the study. Oral immunotherapy for 2 to 5 foods was given daily from week 8 until the end of the study. Omalizumab treatment increased the proportion of patients who passed 2-g food challenges at 36 weeks (83% vs 33%, P = .0044). Importantly, omalizumab treatment had no serious or severe adverse events and had fewer oral immunotherapy doses associated with adverse events (27% vs 68%, P = .0082). These results indicate that omalizumab increases the safety and efficacy of multiple-food oral immunotherapy to induce food allergen desensitization.Omalizumab increases the efficacy of oral immunotherapy to induce food allergen desensitizationR. Sharon ChinthrajahView Large Image Figure ViewerDownload Hi-res image Download (PPT) Omalizumab increases the efficacy of oral immunotherapy to induce food allergen desensitization We asked senior author R. Sharon Chinthrajah, MD, of the Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine, Stanford, California, to comment on the study. She writes, “We are excited about our significant results using this combination approach of omalizumab and multiallergen oral immunotherapy. This could be a very promising way to decrease the burden of living with food allergies.”News items were written by medical writer Jared Travers, PhD.Find more News Beyond Our Pages online at www.jaci-nbop.blogspot.com. News items were written by medical writer Jared Travers, PhD. Find more News Beyond Our Pages online at www.jaci-nbop.blogspot.com.